RESUMEN

This Phase I study was performed to assess the feasibility of combining docetaxel with the new P-glycoprotein inhibitor R101933 and to determine the dose limiting toxicity of this combination. Fifteen patients received oral R101933 alone at a dose escalated from 200 to 300 mg twice daily (b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100 mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and further). Dose limiting toxicity consisting of mucositis and neutropenic fever was reached at the combination of docetaxel, 100 mg/m2, and R101933, 300 mg b.i.d., and the maximum tolerated dose was established at docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of R101933 achieved in patients were in the same range as required in preclinical rodent models to overcome paclitaxel resistance. The plasma pharmacokinetics of docetaxel were not influenced by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 26.5 +/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1 and 2, respectively. These findings indicate that the contribution of a P-glycoprotein inhibitor to the activity of anticancer chemotherapy can now be assessed in patients for the first time independent of its effect on drug pharmacokinetics.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos Fitogénicos/farmacocinética , Benzazepinas/farmacología , Neoplasias/tratamiento farmacológico , Paclitaxel/análogos & derivados , Quinolinas/farmacología , Taxoides , Administración Oral , Adulto , Anciano , Antineoplásicos Fitogénicos/efectos adversos , Área Bajo la Curva , Docetaxel , Relación Dosis-Respuesta a Droga , Fatiga/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/patología , Neoplasias/metabolismo , Neoplasias/patología , Neutropenia/inducido químicamente , Paclitaxel/efectos adversos , Paclitaxel/sangre , Paclitaxel/farmacocinética , Estomatitis/inducido químicamente , Vómitos/inducido químicamente

RESUMEN

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Asunto(s)

Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Quinolonas/uso terapéutico , Administración Oral , Adulto , Anciano , Anemia/inducido químicamente , Disponibilidad Biológica , Médula Ósea/efectos de los fármacos , Cápsulas , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Farnesiltransferasa , Fatiga/inducido químicamente , Femenino , Semivida , Cefalea/inducido químicamente , Humanos , Hipotensión/inducido químicamente , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Náusea/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Quinolonas/efectos adversos , Quinolonas/farmacocinética , Soluciones , Vómitos/inducido químicamente

RESUMEN

Duplicate bioassays for itraconazole and hydroxy-itraconazole were run with 30 serum samples in five laboratories, each using a different method. Both itraconazole and hydroxy-itraconazole were used as standards. Despite quantitative variations, the results of the bioassays correlated sufficiently to indicate the relative level of antifungal activity in the test samples.

Asunto(s)

Antifúngicos/sangre , Cromatografía Líquida de Alta Presión/métodos , Itraconazol/sangre , Bioensayo/métodos , Humanos , Itraconazol/análogos & derivados , Reproducibilidad de los Resultados , Sensibilidad y Especificidad

RESUMEN

Majocchi's granuloma is a folliculitic and perifolliculitic dermatophyte infection of the dermis, a site that is not generally colonized by fungi in immunocompetent individuals. Topical agents are usually ineffective therapeutically because of the deep location of the infection. The objective of this study was to determine the effectiveness of oral itraconazole. We also examined the pharmacokinetics of the drug in scalp hair during pulse therapy. This information would then be useful in determining the efficacy of itraconazole administered by means of intermittent pulse dosing in the treatment of tinea capitis. Seven patients (age range 25-75 years) were treated up to three times with itraconazole pulse therapy, 200 mg twice daily for 1 week, with 2 weeks off between pulses. Samples of scalp hair and plasma were also obtained to determine the pharmacokinetics of the drug at these two sites. All seven patients responded to therapy, clinical and mycological cure being achieved after one pulse (one patient), two pulses (three patients), or three pulses (three patients, each with toenail onychomycosis); none relapsed over a 6-18-month follow-up period. In all six patients who received two or more pulses of itraconazole, almost complete cure was observed before the second pulse, with full resolution within 2 weeks of its completion. Itraconazole was also detected in the hair after 1 week, and at concentrations 2.6-fold and 3.4-fold higher, respectively, after the second and third pulses. After the discontinuation of therapy, itraconazole was then detectable in the hair for 9 months, at least in a female patient who did not have her hair cut. Two pulses of oral itraconazole therapy thus appear to be effective in the treatment of Majocchi's granuloma, and it is possible that one pulse may be sufficient in some patients. These data suggest that itraconazole pulse therapy should be effective in the treatment of tinea capitis.

Asunto(s)

Antifúngicos/uso terapéutico , Granuloma/tratamiento farmacológico , Itraconazol/uso terapéutico , Tiña/tratamiento farmacológico , Adulto , Anciano , Antifúngicos/farmacocinética , Esquema de Medicación , Femenino , Granuloma/metabolismo , Humanos , Itraconazol/farmacocinética , Masculino , Persona de Mediana Edad , Tiña/metabolismo , Tiña del Cuero Cabelludo/tratamiento farmacológico , Tiña del Cuero Cabelludo/metabolismo

RESUMEN

The single-dose pharmacokinetics of lubeluzole were investigated in 2 single-blind, placebo-controlled, dose-escalation studies in healthy male subjects. In the first study, 6 subjects received an intravenous infusion of 2.5, 5, and 10 mg lubeluzole. In the second study, a 15 mg dose of lubeluzole was administered to 6 subjects, of whom 5 also received 20 mg and 2 also 25 mg lubeluzole. Following the infusion, plasma lubeluzole concentrations decayed biphasically, with a mean distribution half-life (t1/2alpha) of 30 to 65 minutes and a mean terminal half-life (t1/2beta) of 15 to 24 hours. The results of the 2 studies indicate that lubeluzole exhibits linear kinetics over the dose range tested in healthy male subjects.

Asunto(s)

Fármacos Neuroprotectores/farmacocinética , Piperidinas/farmacocinética , Tiazoles/farmacocinética , Adulto , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/sangre , Piperidinas/administración & dosificación , Piperidinas/sangre , Método Simple Ciego , Tiazoles/administración & dosificación , Tiazoles/sangre

RESUMEN

The dose proportionality of lubeluzole, a drug in clinical development for the treatment of acute ischemic stroke, was evaluated in a Phase I, single-center, open-label, randomized-dosing-sequence, three-way crossover clinical trial in 12 healthy adults. An equal number of male and female volunteers were enrolled in the trial, with a mean weight (+/- SD) of 73.2 +/- 11.9 kg, mean height (+/- SD) of 66.8 +/- 4.6 inches, and a mean age of 36.1 +/- 5.2 years. Subjects received intravenous infusions of 5 (A), 10 (B), and 15 mg (C) of lubeluzole over 1 hour on three separate occasions, with a minimum washout period of 2 weeks. The treatment sequences were A-B-C; A-C-B; B-A-C; B-C-A; C-A-B; and C-B-A. One male and one female were assigned to each sequence. After the 5-, 10-, and 15-mg doses, maximum concentration (Cmax) was 58.1, 113, and 138 microg/L, respectively, and the area under the curve from 0 to (AUC(0-infinity)) was 771, 1384, and 2025 microg x h/L. There were no statistically significant differences among the groups in mean terminal half-life, steady-state volume of distribution, total plasma clearance, or dose-normalized AUC(0-infinity). Dose-normalized values of Cmax differed significantly between the groups. No serious adverse events were reported, and no changes were observed in cardiac function, as judged by the QT(c) interval. The pharmacokinetics of lubeluzole appear to be linear at intravenous infusion doses of 5, 10, and 15 mg, and these doses are well tolerated by healthy adults.

Asunto(s)

Fármacos Cardiovasculares/administración & dosificación , Fármacos Cardiovasculares/farmacocinética , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Tiazoles/administración & dosificación , Tiazoles/farmacocinética , Adulto , Fármacos Cardiovasculares/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Masculino , Fármacos Neuroprotectores/efectos adversos , Piperidinas/efectos adversos , Tiazoles/efectos adversos

RESUMEN

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.

Asunto(s)

Síndrome de Inmunodeficiencia Adquirida/metabolismo , Antifúngicos/farmacocinética , Itraconazol/farmacocinética , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Administración Oral , Adulto , Anciano , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Antifúngicos/sangre , Ciclodextrinas/sangre , Ciclodextrinas/farmacocinética , Ciclodextrinas/orina , Femenino , Humanos , Inyecciones Intravenosas , Itraconazol/administración & dosificación , Itraconazol/efectos adversos , Itraconazol/análogos & derivados , Itraconazol/sangre , Masculino , Persona de Mediana Edad

RESUMEN

Loperamide, a peripherally acting opiate receptor agonist with antidiarrheal action, inhibits ileal and colonic motor function. It was determined whether loperamide also affects gallbladder emptying and pancreatic enzyme secretion in humans. Plasma cholecystokinin (radioimmunoassay), gallbladder volume (ultrasonography), and intraduodenal bilirubin and amylase output (spot sampling) were measured at regular intervals before and during intraduodenal perfusion of an amino acid meal in 8 healthy subjects: once without and once with pretreatment of 8 mg loperamide, ingested 13 and 4 hours before the start of the meal. Loperamide decreased basal amylase output from 3.2 +/- 0.5 to 1.0 +/- 0.5 kU/h (P < .005) and abolished basal bilirubin output (21 +/- 5 vs. 0 +/- 0 micromol/h; P < .005) into the duodenum. Loperamide increased basal gallbladder volume from 28 +/- 4 to 39 +/- 4 mL (P < .0001) but was without effect on basal plasma cholecystokinin (2.7 +/- 0.3 vs. 3.0 +/- 0.3 pmol/L). During the amino acid meal, pretreatment with loperamide inhibited amylase output from 5.1 +/- 0.8 to 1.6 +/- 0.4 kU/h (P < .001), bilirubin output from 39 +/- 6 to 18 +/- 6 micromol/h (P < .0005) and gallbladder contraction from 47% +/- 3% to 26% +/- 6% (P < .05), whereas loperamide enhanced amino acid-stimulated plasma cholecystokinin from 4.5 +/- 1.6 to 7.6 +/- 1.0 pmol/L (P < .05). It is concluded that loperamide inhibits basal and amino acid-stimulated gallbladder motility and intraduodenal output of bilirubin and amylase, despite an enhanced postprandial cholecystokinin release.

Asunto(s)

Antidiarreicos/farmacología , Vesícula Biliar/efectos de los fármacos , Loperamida/farmacología , Páncreas/efectos de los fármacos , Adulto , Bilirrubina/metabolismo , Colecistoquinina/sangre , Femenino , Humanos , Loperamida/sangre , Masculino

RESUMEN

AIMS: To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured adenosine breakdown inhibition (ABI). METHODS: Draflazine was administered to healthy volunteers as a 15-min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately followed by an infusion of the same dose over 1 h. Plasma and whole blood concentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The capacity-limited specific binding of draflazine to the nucleoside transporter located on the erythrocytes was evaluated by a population approach. RESULTS: The estimate of the population parameter typical value (%CV) of the binding constant Kd and the maximal specific binding capacity (Bmax) was 0.385 (3.5) ng ml-1 plasma and 158 (2.1) ng ml-1 RBC, respectively. The non-specific binding was low. The specific binding to the erythrocytes was a source of non-linearity in the pharmacokinetics of draflazine. The total plasma clearance of draflazine slightly decreased with increasing doses, whereas the total clearance in whole blood increased with increasing doses. The sigmoidal Emax equation was used to relate the plasma and whole blood concentration of draflazine to the ex vivo determined ABI. In plasma, typical values (%CV) of Emax, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml-1 and 1.06 (3.4), respectively. The relationship in whole blood was much steeper with population parameter typical values (%CV) of Emax, IC50 and Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml-1 and 4.47 (5.5), respectively. The RBC occupancy of draflazine did not coincide with the ex vivo measured ABI. The observed relationship between RBC occupancy and ABI was not directly proportional but similar for all studied infusion schemes. CONCLUSIONS: The findings of this study show that the occupancy of the nucleoside transporter by draflazine should be at least 90% in order to inhibit substantially adenosine breakdown in vivo. On the basis of these findings it is suggested that a 15 min infusion of 1 mg draflazine followed by an infusion of 1 mg h-1 could be appropriate in patients undergoing a coronary artery bypass grafting.

Asunto(s)

Eritrocitos/metabolismo , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Adenosina/sangre , Adulto , Área Bajo la Curva , Unión Competitiva , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Recuento de Eritrocitos/efectos de los fármacos , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Semivida , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación , Piperazinas/sangre , Piperazinas/farmacología , Inhibidores de Agregación Plaquetaria/sangre , Inhibidores de Agregación Plaquetaria/farmacología , Análisis de Regresión , Programas Informáticos , Población Blanca

RESUMEN

The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.

Asunto(s)

Antipsicóticos/farmacocinética , Risperidona/farmacocinética , Adulto , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Disponibilidad Biológica , Estudios Cruzados , Humanos , Isoxazoles/farmacocinética , Masculino , Palmitato de Paliperidona , Pirimidinas/farmacocinética , Risperidona/administración & dosificación , Risperidona/efectos adversos , Soluciones , Comprimidos , Equivalencia Terapéutica

RESUMEN

AIMS: The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. METHODS: Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. RESULTS: Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml-1) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml-1 h) and from 0 to infinity (17.4 to 48.2 ng ml-1 h), and the elimination half-life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. CONCLUSIONS: Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.

Asunto(s)

Antifúngicos/farmacología , Astemizol/farmacocinética , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Itraconazol/farmacología , Administración Oral , Adulto , Análisis de Varianza , Astemizol/farmacología , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Modelos Lineales , Masculino

RESUMEN

OBJECTIVE: The pharmacokinetics of a single i.v. dose of the new racemic beta-adrenoceptor-blocker nebivolol [0.073 mg base.kg-1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). METHODS: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4-5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. RESULTS: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (Vss) 673 l; volume corrected by real body weight (Vss.kg-1) 11.2 l.kg-1; total clearance (CL) 51.6 h-1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l.h-1) were significantly higher in obese patients. But Vss.kg-1 (9.4 l.kg-1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l.h-1) and the t1/2 prolonged (32-34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. CONCLUSION: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.

Asunto(s)

Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacocinética , Benzopiranos/farmacología , Benzopiranos/farmacocinética , Etanolaminas/farmacología , Etanolaminas/farmacocinética , Obesidad/metabolismo , Obesidad/fisiopatología , Adulto , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Lípidos/sangre , Masculino , Nebivolol

RESUMEN

OBJECTIVE: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22-55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg.h-1) and variable duration (2-24 h). METHODS: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. RESULTS: The population typical value for the dissociation constant Kd (%CV) was 0.648 (12) ng.ml-1 plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity Bmax (%CV) was 155 (2) ng.ml-1 RBC. The interindividual variability (%CV) was moderate for Kd (38.9%) and low for Bmax (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t1/2 beta averaged 11.0-30.5 h and the mean CL from the plasma was 327 to 465 ml.min-1. The disposition of draflazine in whole blood was different from that in plasma. The mean t1/2 beta was 30.2 to 42.2 h and the blood CL averaged 17.4-35.6 ml.min-1. CONCLUSION: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg.h-1, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients.

Asunto(s)

Cardiotónicos/farmacocinética , Eritrocitos/metabolismo , Piperazinas/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Adulto , Cardiotónicos/administración & dosificación , Cardiotónicos/sangre , Proteínas Portadoras/antagonistas & inhibidores , Método Doble Ciego , Femenino , Humanos , Infusiones Intravenosas , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Persona de Mediana Edad , Proteínas de Transporte de Nucleósidos , Piperazinas/administración & dosificación , Piperazinas/sangre , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/sangre

RESUMEN

Pharmacokinetics and safety of a hydroxy-beta-propyl solution of itraconazole were assessed in 16 patients in an intensive care unit. On the first 2 days, four 1-h infusions of 200 mg were given at 0, 8, 24, and 32 h. From day 3 to 7, inclusive, a single 1-h infusion of 200 mg of itraconazole was given daily. The intravenous (i.v.) treatment was directly followed by repeated administrations of an oral solution of itraconazole at a dosage of either 200 mg once daily or 200 mg twice daily (b.i.d.). During i.v. treatment, steady-state concentrations of itraconazole and hydroxy-itraconazole in plasma were reached within 48 and 96 h, respectively. At the end of i.v. treatment, mean (+/- standard deviation) itraconazole and hydroxy-itraconazole trough concentrations in plasma were 0.344 +/- 0.140 and 0.605 +/- 0.205 microg/ml, respectively. After the 2-week oral follow-up of 200 mg once daily the mean trough concentration had decreased to 0.245 microg/ml, whereas after 200 mg b.i.d. it increased to 0.369 microg/ml. Diarrhea during oral treatment appeared to be dose related and may be due to the solvent hydroxypropyl-beta-cyclodextrin. More severe laboratory abnormalities were noted during the i.v. than the oral treatment phase, probably related to more severe illness in that period of intensive care, but none proved clinically important. These results suggest that plasma itraconazole levels above 0.250 microg/ml may be achieved and maintained with the 1-week i.v. schedule followed by b.i.d. oral administration, whereas the once-daily oral follow-up seems to be a suboptimal treatment.

Asunto(s)

Antifúngicos/efectos adversos , Antifúngicos/sangre , Itraconazol/efectos adversos , Itraconazol/sangre , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Adolescente , Adulto , Antifúngicos/uso terapéutico , Ciclodextrinas/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Unidades de Cuidados Intensivos , Itraconazol/análogos & derivados , Itraconazol/uso terapéutico , Masculino , Persona de Mediana Edad , Micosis/prevención & control , Soluciones

RESUMEN

A total of 22 patients with acute ischemic stroke participated in two randomized, single-masked, placebo-controlled studies that evaluated the safety and pharmacokinetics of single escalating intravenous doses of lubeluzole. The first dose of study medication in all patients was given within 6 hours of the first sign of stroke onset. In the first study, 6 patients received a single 1-hour intravenous infusion of 5 mg of lubeluzole; 4 of these patients received an additional 10-mg dose 3 to 4 days later. Two additional patients received placebo. In the second study, 4 patients received a single 1-hour infusion of 10 mg of lubeluzole, and 2 patients received placebo. After a safety evaluation of the second study, 6 additional patients received 15 mg of lubeluzole, and 2 other patients received placebo. Lubeluzole had no clinically relevant effects on any cardiovascular variable compared with placebo. The majority of adverse experiences were mild to moderate and resolved during treatment. No unexpected electroencephalogram abnormalities were observed, and no evidence of epileptiform discharges was found in any of the patients. At the end of the infusion, plasma lubeluzole concentrations decayed biphasically, with mean distribution half-lives of 46.3 to 101.0 minutes and mean terminal half-lives of 20.8 to 27.7 hours. Comparisons of the dose-normalized value of the individual plasma concentrations at the end of the infusion and the total area under the curve from time 0 to infinity suggested that lubeluzole exhibited linear kinetics over the dose range evaluated in patients with ischemic stroke. In the small number of patients studied, lubeluzole's favorable safety profile was demonstrated by the lack of clinically relevant effects on cardiovascular variables and by neurologic examination and clinical laboratory findings.

Asunto(s)

Trastornos Cerebrovasculares/metabolismo , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/farmacocinética , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Anciano , Electrocardiografía/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Método Simple Ciego

RESUMEN

1. Draflazine, a nucleoside transport inhibitor, was administered as a 15 min i.v. infusion of 2.5 mg to eight healthy male subjects. Plasma and whole blood concentrations were measured up to 32 h post-dose, and were related to adenosine breakdown inhibition (ABI) measured ex vivo, which served as a pharmacodynamic endpoint. 2. The red blood cell/plasma distribution of draflazine was non-linear and characterized as a capacity-limited specific binding to the nucleoside transporter on the red blood cells. The binding (dissociation) constant Kd was 0.87 ng ml-1 plasma and the maximal specific binding capacity (Bmax) was 164 ng ml-1 RBC, which corresponds to about 14,000 specific binding sites per erythrocyte. Non-specific binding amounted to less than 15% of the total binding. 3. The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pharmacokinetic model. The pharmacokinetic parameters (mean +/- s.d.) were: clearance 22.0 +/- 8.0 ml mm-1, volume of distribution at steady-state 39.8 +/- 4.7 l and terminal half-life 24.0 +/- 9.4 h. Concentrations in plasma were much lower, and could only be determined accurately in pooled plasma samples with a red blood cell binding assay. The pharmacokinetic parameters in pooled plasma were: clearance 551 ml min-1, volume of distribution at steady-state 349 l and terminal half-life 10.7 h. 4. A non-linear relationship was observed between the plasma or blood concentration of draflazine and the ABI determined ex vivo. This relationship was characterized by the sigmoidal Emax pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were Emax 100%, IC50 10.5 ng ml-1 and Hill factor 0.9. When using whole blood concentrations, the relationship was much steeper with values (mean +/- s.d.) Emax 92.4 +/- 5.6%, IC50 76.0 +/- 15.3 ng ml-1 and Hill factor 3.5 +/- 0.9. 5. Binding to the nucleoside transporter on red blood cells is an important determinant of the pharmacokinetics of draflazine and a high degree of occupancy of the transporter by draflazine is required to inhibit adenosine breakdown ex vivo. It is suggested that red blood cell nucleoside transporter occupancy may serve as a useful pharmacodynamic endpoint in dose ranging studies with draflazine.

Asunto(s)

Proteínas Portadoras/antagonistas & inhibidores , Eritrocitos/metabolismo , Proteínas de la Membrana/antagonistas & inhibidores , Piperazinas/farmacocinética , Adenosina/metabolismo , Adulto , Proteínas Portadoras/metabolismo , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Nucleósidos , Piperazinas/farmacología

RESUMEN

In a double-blind, randomized study in patients undergoing thoracic surgery the plasma and cerebrospinal fluid (CSF) pharmacokinetics of the epidural sufentanil were studied by using radioimmunoassay analysis. Sufentanil was given as an infusion (1 microgram/mL) at the lumbar (Ls; n = 11), or thoracic (Ts; n = 12) level, or epidural sufentanil combined with bupivacaine (1 mg/ mL) at the thoracic level (Tsb; n = 14). Postoperatively, the infusion was adjusted to optimize analgesia. During the infusion, the sufentanil plasma concentrations were related to the rate of epidural infusion and unrelated both to the epidural infusion regimen and to the postoperative pain scores. The elimination half-life in plasma (mean +/- SEM) was 9.9 +/- 1.7 h (Ls), 8.6 +/- 0.7 h (Ts), and 11.7 +/- 2.2 h (Tsb). The distribution volume was 15.2 +/- 3.5 l/kg (Ls), 14.8 +/- 2.4 L/kg (Ts), and 12.9 +/- 1.2 L/kg (Tsb). Total sufentanil clearance was 17.8 +/- 1.4 and 16.9 +/- 2.0 mL.kg-1.min-1 (Ls), 22.9 +/- 3.5 and 20.0 +/- 2.6 mL.kg-1.min-1 (Ts), and 22.4 +/- 3.0 and 14.5 +/- 1.3 mL.kg-1.min-1 (Tsb). The terminal elimination half-life of sufentanil in CSF was 7.2 +/- 0.6 h. During steady state the CSF concentrations were not homogeneously distributed and they were higher than those in plasma. These pharmacokinetic findings support the concept that epidural sufentanil analgesia is optimal when administered segmentally and tailored to the surgical incision.

Asunto(s)

Analgesia Epidural , Analgésicos Opioides/farmacocinética , Anestesia Epidural , Anestésicos Locales/farmacocinética , Bupivacaína/farmacocinética , Sufentanilo/farmacocinética , Toracotomía , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/sangre , Analgésicos Opioides/líquido cefalorraquídeo , Anestésicos Locales/administración & dosificación , Anestésicos Locales/sangre , Anestésicos Locales/líquido cefalorraquídeo , Bupivacaína/administración & dosificación , Bupivacaína/sangre , Bupivacaína/líquido cefalorraquídeo , Método Doble Ciego , Semivida , Humanos , Tasa de Depuración Metabólica , Dimensión del Dolor , Dolor Postoperatorio/prevención & control , Sufentanilo/administración & dosificación , Sufentanilo/sangre , Sufentanilo/líquido cefalorraquídeo

RESUMEN

STUDY OBJECTIVE: To compare the pharmacokinetics of a single 100-mg oral dose of itraconazole administered as 10 ml of a 10-mg/ml itraconazole solution in hydroxypropyl-beta-cyclodextrin under fasting versus postprandial conditions. DESIGN: Open-label, two-way, randomized, crossover study. SETTING: Janssen Research Foundation, Belgium. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Blood samples were obtained for pharmacokinetic analyses immediately before dosing and at regular intervals up to 96 hours after each dose. Blood and urine samples were obtained for hematologic, biochemical, and urinary safety analyses at baseline and at the end of the study. MEASUREMENTS AND MAIN RESULTS: The mean peak plasma concentrations of both itraconazole and its active metabolite hydroxy-itraconazole were significantly higher under fasting conditions than under postprandial conditions. The mean times to peak concentration for both the parent compound and its metabolite were significantly shorter under fasting than under nonfasting conditions. The mean areas under the curve (AUC0-infinity and AUC0-24 hrs) were also significantly higher under fasting than under postprandial conditions. CONCLUSIONS: Our findings suggest that the higher bioavailability of this new formulation of itraconazole may be of benefit in seriously ill patients who are not able to ingest adequate quantities of food. The fact that the solution was also well tolerated and was not associated with clinically significant changes in any laboratory value further underscores the potential utility of this dosing form.

Asunto(s)

Antifúngicos/farmacocinética , Dextrinas/administración & dosificación , Interacciones Alimento-Droga , Itraconazol/farmacocinética , Adulto , Análisis de Varianza , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Antifúngicos/orina , Estudios Cruzados , Formas de Dosificación , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Itraconazol/administración & dosificación , Itraconazol/sangre , Itraconazol/orina , Masculino , Persona de Mediana Edad

RESUMEN

BACKGROUND AND DESIGN: In the treatment of onychomycosis, oral therapies have generally been given as a continuous-dosing regimen. For example, the suggested dose of itraconazole for the treatment of onychomycosis has thus far been 200 mg/d for 3 months. Based on the advances in our understanding of the pharmacokinetics of itraconazole, we investigated the efficacy and nail kinetics of intermittent pulse-dosing therapy with oral itraconazole in patients who were suffering from onychomycosis. Fifty patients with confirmed onychomycosis of the toenails, predominantly Trichophyton rubrum, were recruited and randomly assigned to three (n = 25) or four (n = 25) pulses of 1-week itraconazole therapy (200 mg twice daily for each month). Clinical and mycological evaluation of the infected toenails, and determination of the drug levels in the distal nail ends of the fingernails and toenails, were performed at the end of each month up to month 6 and then every 2 months up to 1 year. RESULTS: In the three-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 67 (month 1) to 471 (month 6) ng/g, and in the distal ends of the fingernails, it ranged from 103 (month 1) to 424 (month 6) ng/g. At month 11, the drug was still present in the distal ends of the toenails at an average concentration of 186 ng/g. The highest individual concentrations of 1064 and 1166 ng/g were reached at month 6 for toenails and fingernails, respectively. At end-point follow-up, toenails in 84% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. In the four-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 32 (month 1) to 623 (month 8) ng/g, and in the distal ends of the fingernails, it ranged from 42 (month 1) to 380 (month 6) ng/g. The highest individual concentrations of 1549 and 946 ng/g were reached at month 7 for toenails and at month 9 for fingernails, respectively. At month 12, the drug was still present in the distal ends of the toenails at an average concentration of 196 ng/g. At end-point follow-up, toenails in 76% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. There were no significant intergroup differences between the three- and four-pulse treatment groups for the primary efficacy parameters. The drug was well tolerated with no significant side effects in either patient group. CONCLUSIONS: Following pulse therapy with itraconazole (400 mg/d given for 1 week each month for 3 to 4 months), the drug has been detected in the distal ends of nails after the first pulse, and it has reached therapeutic concentrations with further therapy. After stopping the last pulse, the drug remains in the nail plate at levels above 300 ng/g for several months. Clinical cure rates between 76% and 84% and negative mycological examination findings between 72% and 80%, respectively, were observed in toenail onychomycosis. The data suggest that pulse therapy with itraconazole is an effective and safe treatment option for onychomycosis.

Asunto(s)

Antifúngicos/administración & dosificación , Itraconazol/administración & dosificación , Onicomicosis/tratamiento farmacológico , Anciano , Análisis de Varianza , Antifúngicos/farmacocinética , Distribución de Chi-Cuadrado , Esquema de Medicación , Femenino , Estudios de Seguimiento , Dermatosis del Pie/tratamiento farmacológico , Dermatosis del Pie/metabolismo , Dermatosis del Pie/microbiología , Dermatosis de la Mano/tratamiento farmacológico , Dermatosis de la Mano/metabolismo , Dermatosis de la Mano/microbiología , Humanos , Itraconazol/farmacocinética , Masculino , Uñas/metabolismo , Uñas/microbiología , Onicomicosis/metabolismo , Onicomicosis/microbiología , Trichophyton/aislamiento & purificación

RESUMEN

The pharmacokinetics of the antipsychotic agent risperidone were investigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparative trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone and the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma protein binding were observed in hepatic and renal disease, whereas the protein binding was not influenced by aging. The inter-individual variability in plasma concentrations of the active moiety was much less than the variability in plasma concentrations of risperidone. Three out of six subjects, behaving like poor metabolizers, were on medication (thiethylperazine, amitriptyline, metoprolol) that may inhibit risperidone metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokinetics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced in renal disease patients. The elimination rate and clearance of 9-hydroxy-risperidone was reduced in elderly and renal disease patients because of a diminished creatinine clearance. The CL(oral) of the active moiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addition, the t1/2 of the active moiety was prolonged (19 h in young subjects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients with renal disease. In cirrhotic patients, the single-dose pharmacokinetics were comparable to those in healthy young subjects.

Asunto(s)

Antipsicóticos/farmacocinética , Fallo Renal Crónico/fisiopatología , Cirrosis Hepática/fisiopatología , Risperidona/farmacocinética , Adulto , Factores de Edad , Anciano , Proteínas Sanguíneas/metabolismo , Femenino , Semivida , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/orina , Cirrosis Hepática/sangre , Cirrosis Hepática/orina , Masculino , Persona de Mediana Edad , Unión Proteica , Risperidona/sangre , Risperidona/orina , Albúmina Sérica/metabolismo